Mar 15, 2019 Taking a deeper look at activated PI3K-delta syndrome

Researchers in Japan identify a new causative gene for APDS and continue to assess effective treatment strategies

Arrows point to the life-threatening proliferation of lymphocytes found in a patient with APDS (left two images),
which are reduced following treatment (right two images)

Reproduced with permission from reference two © 2018  American Academy of Allergy, Asthma & Immunology

A rare disorder that disrupts the immune system, known as activated PI3K-delta syndrome or APDS, was described in 2013 by a team led by Ivan Angulo at the University of Cambridge. Since then, international efforts have rapidly built knowledge of causes, mechanisms and treatments for this disorder.

Patients with APDS have low immunoglobulin levels and are susceptible to recurrent respiratory tract infections. In some cases, they may suffer from severely swollen lymph nodes or spleen that can be life-threatening.

Understanding of APDS is progressing rapidly, with researchers in Japan contributing to this knowledge base in a number of ways. In 2016, a multi-institutional collaboration, led by Yuki Tsujita of the National Defense Medical College, showed for the first time that mutations in a gene called PTEN can cause APDS-like immunodeficiency1.

“Our results indicated that PTEN loss-of-function mutations can also cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes,” says Kohsuke Imai, a corresponding author of the study based at the Tokyo Medical and Dental University (TMDU). Much remains to be explored, he adds, as not all patients with PTEN mutations develop APDS and more studies are needed to clarify the underlying immunological mechanisms.

Imai, with Tsubasa Okano from TMDU, also led a 2019 study involving researchers in Japan, Taiwan and France that highlighted the need to keep refining methods for hematopoietic stem cell transplantation (HSCT) as an effective curative treatment for APDS2.

HSCT is currently considered by general practitioners as a promising way to put the brakes on disease progression and associated malignancy. However, the study, which focused on 23 patients with APDS including nine patients who underwent HSCT, indicated the high rate of adverse effects that can arise: including graft failure and rejection in 90 percent of cases studied. The researchers therefore recommend the need to develop molecular targeted drugs such as rapamycin or PI3K delta inhibitors as well as better practices and procedures in HSCT. Above all, they encourage early consultation with general practitioners to reduce the risk of life-threatening complications.

To date, more than 350 human genes have been associated with various primary immunodeficiency diseases (PIDs). Given the speed at which 23 cases of APDS were diagnosed in a short span of time in the 2019 study, Imai says there may be a considerable number of yet undiagnosed cases in Japan.

Imai and colleagues are continuing to update the Primary Immunodeficiency Database in Japan (PIDJ) and share findings through collaborations with the Japanese Society for Immunodeficiency and Autoinflammatory Diseases (JSIAD) at a national level and the International Alliance for Primary Immunodeficiency Societies (IAPIDS) at an international level. Through these efforts, they expect to develop more accurate methods of diagnosis, construct predictive models and find the most appropriate treatments for these diseases.

The program-affiliated researchers contributing to this research are from the Department of Pediatrics, Tokyo Medical and Dental University, Japan.


  1. Tsujita, Y., Mitsui-Sekinaka, K., Imai, K., Yeh, T.-W., Mitsuiki, N. et al. Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome–like immunodeficiency. The Journal of Allergy and Clinical Immunology 138, 1672–1680.e10 (2016). | Article
  2. Okano, T., Imai, K., Tsuijita, Y., Mitsuiki, N., Yoshida, K. et al. Hematopoietic stem cell transplantation for progressive combined immunodeficiency and lymphoproliferation in patients with activated phosphatidylinositol-3-OH kinase δ syndrome type 1. The Journal of Allergy and Clinical Immunology 143, 266–275 (2019). | Article

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